辛伐他汀可发挥抗淀粉样蛋白β25-35 注射诱导的小鼠健忘作用。
Simvastatin exerts antiamnesic effect in Aβ25-35 -injected mice.
机构信息
Department of Physiology, Nanjing Medical University, Nanjing, China; Department of Geriatric Neurology, Jiangsu Province Hospital, Nanjing, China.
出版信息
CNS Neurosci Ther. 2014 Mar;20(3):218-26. doi: 10.1111/cns.12190. Epub 2013 Dec 2.
AIM AND METHODS
Simvastatin (SV) is reported to improve cognition and slow the progression of Alzheimer's disease (AD). This study explored the mechanisms underlying the antiamnesic effect of SV in AD using behavior tests, histological examination, western blot analysis, and electrophysiological recording technique in AD model mice created by intracerebroventricular injection (i.c.v.) of Aβ25-35 .
RESULTS
Chronic administration of SV (40 mg/kg/day) for 11 days after Aβ25-35 -injection ameliorated the impairment of acquisition performance and probe trail test in Morris water maze task and alternation behavior in Y maze task in Aβ25-35 -mice. Aβ25-35 -induced apoptosis of hippocampal CA1 pyramidal cells and Aβ25-35 -impaired high-frequency stimulation (HFS)-dependent long-term potentiation (LTP) induction in hippocampal Schaffer collaterale-CA1 synapse were rescued by SV-treatment. SV prevented Aβ25-35 -inhibited protein kinase B (Akt) and extracellular signal-related kinase-2 (ERK2) phosphorylation, which was sensitive to α7 nicotinic acetylcholine receptor (α7nAChR) antagonist MLA. SV-induced neuroprotection was attenuated by MLA or phosphatidylinositol-3-kinase (PI3K) antagonist LY294002. SV-rescued LTP induction was blocked by α7nAChR, PI3K or MAPK/ERK kinase (MEK) antagonist. Finally, the antiamnesia of SV in Aβ25-35 -mice was attenuated by blockage of SV-induced neuroprotection or SV-rescued LTP induction.
CONCLUSION
The antiamnesia of SV in Aβ25-35 -mice depends on its neuroprotection and synaptic plasticity improvement.
目的和方法
辛伐他汀（SV）被报道可改善认知功能并减缓阿尔茨海默病（AD）的进展。本研究通过β淀粉样蛋白（Aβ）25-35 脑室内注射（i.c.v.）构建 AD 模型小鼠，采用行为学测试、组织学检查、western blot 分析和电生理记录技术，探讨了 SV 抗 AD 记忆障碍的机制。
结果
SV（40mg/kg/天）慢性给药 11 天，可改善 Aβ25-35 注射后 Morris 水迷宫任务中获得性表现和探测试验以及 Y 迷宫任务中交替行为的损伤。SV 可挽救 Aβ25-35 诱导的海马 CA1 锥体神经元凋亡和 Aβ25-35 损害的海马 Schaffer 侧支-CA1 突触高频刺激（HFS）依赖性长时程增强（LTP）诱导。SV 可阻止 Aβ25-35 抑制蛋白激酶 B（Akt）和细胞外信号调节激酶-2（ERK2）磷酸化，该作用对α7 烟碱型乙酰胆碱受体（α7nAChR）拮抗剂 MLA 敏感。MLA 或磷脂酰肌醇-3-激酶（PI3K）拮抗剂 LY294002 减弱了 SV 诱导的神经保护作用。SV 挽救的 LTP 诱导被 α7nAChR、PI3K 或丝裂原活化蛋白激酶/细胞外信号调节激酶激酶（MEK）拮抗剂阻断。最后，SV 诱导的神经保护或 SV 挽救的 LTP 诱导阻断，减弱了 SV 在 Aβ25-35 小鼠中的抗记忆障碍作用。
结论
SV 在 Aβ25-35 小鼠中的抗记忆障碍作用依赖于其神经保护和突触可塑性改善。
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